Skeletal muscle vascular beds exhibit a graded vasodilation and elevated blood flow in response to hypoxia as well as during dynamic exercise. Interestingly, the combination of exercise and hypoxia produces a "compensatory" vasodilator response and an even greater hyperemic response compared to exercise under control conditions in humans. The mechanisms responsible for the compensatory vasodilation and maintained O2 delivery to contracting muscles during exercise with hypoxia remain unclear. It is generally accepted that adenosine plays a major role in hypoxia-induced skeletal muscle vasodilation but does not appear to be obligatory during exercise hyperemia. In this context, this application addresses the overall hypothesis that adenosine participates in the compensatory vasodilator responses seen during exercise by addressing the following specific aims. First, whether adenosine and nitric oxide are obligatory for the compensatory vasodilation during hypoxic exercise. Second, determine the possible contribution of ATP released from erythrocytes during hypoxic exercise has on the adenosine(ADO) mediated compensatory vasodilaton. Third, it is not known if aging blunts the compensatory vasodilator response during hypoxic exercise or if the mechanisms that promote vasodilation during hypoxic exercise are the same or different than those in younger individuals. In addition, these aims will serve as an ideal postdoctoral training vehicle for the proponent and represent a significant extension and expansion of his current skill set using approaches that are well established in the sponsor's laboratory. The strength of the proposed experimental design is that we will study the basic mechanisms of circulatory control during hypoxic exercise in humans. The results of these experiments will provide important new information about the metabolic regulation of skeletal muscle blood flow in humans. The ability to perform physical activity and exercise are or should be essential components of everyday life. For exercise to be performed there must be adequate blood flow to the exercising muscles. This proposal seeks to study the factors that cause blood flow to rise in exercising muscles and how these factors might be influenced by low levels of oxygen. We also seek to study these events in aging humans because older humans sometimes have diseases or conditions that result in low levels of oxygen in the blood. J